Project Summary Immunosenescence defines the changes in the immune system associated with age that are responsible for the age-dependent defects in the ability to respond to pathogens and develop effective responses to vaccination in the elderly. Both the innate and the adaptive immune system show functional defects with age, with T cells' function being specially affected. The molecular mechanisms that are responsible for defective T cell function are however not yet fully understood. Lysosomal degradation of proteins via autophagy has been shown to play a key role in maintaining normal cell homeostasis by reducing the accumulation of damaged proteins. Autophagy also plays an important role in the regulation of cell protein levels in response to extracellular signals, and has been implicated in the control of T cell homeostasis. In collaboration with P1 and P2 in this Program Project (PP), we have shown that macroautophagy and chaperone mediated autophagy are both activated in response to TCR engagement and play key roles in the regulation of the maintenance of the bioenergetics output in activated T cells and in the regulation of signaling cascades downstream of the TCR, respectively. Interestingly the activity of these pathways is reduced in T cells from aged mice and its restoration leads to improve activation-induced responses in aged T cells. Furthermore, working with P4 we have found that the activity of both pathways appears to respond to lipid and oxidative stress, both characteristic of the aging process. In this proposal we intend to elucidate the molecular mechanisms that regulate the different forms of autophagy in T cells and characterize how the age-associated decline in autophagy may determine the development of deficient T cell responses. We will also study how increased chronic pathogen, lipid and oxidative stress in aging may contribute to the decreased activity of macroautophagy and/or chaperone mediated autophagy with age. Finally, using mouse models, we will study the possibility ofrestoring autophagic activity in old rodents to improve T cell-mediated responses in vivo. Relevance: Understanding the molecular mechanism that are responsible for reduced immunity in old organisms should prove valuable in the development of new therapeutic interventions aimed at restoring normal immune function and therefore reduce morbidity and mortality in the elderly. .